An Adipocyte MKK3–p38β Axis Preserves Insulin Responsiveness in Mice and Is Reciprocally Altered in Human Obesity
ABSTRACT Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipocyte stress responses can either promote metabolic dysfunction or preserve insulin action, but the contribution of the p38 MAPK activator MKK3 to adipose tissue physiology remains poorly understood. Here, we show that adipose MKK3 expression increases early during high‐fat feeding and is also elevated in human obesity. In human visceral adipose tissue, MKK3 expression was positively associated with body mass index and leptin and inversely associated with HbA1c in unadjusted analyses. Using germline, Fabp4‐Cre, and Adipo‐Cre Mkk3‐deficient mice, together with p38β‐deficient mice and primary adipocytes, we found that loss of adipocyte MKK3 impairs insulin responsiveness. Adipo‐Cre;Mkk3 fl/fl (Adipo Mkk3 ) mice displayed reduced insulin‐stimulated glucose uptake selectively in subcutaneous white adipose tissue despite unchanged body composition and basal brown adipose tissue activity. Mechanistically, MKK3 or p38β deficiency increased p70S6K activity and inhibitory IRS1 Ser307 phosphorylation, reduced GLUT4 translocation and Akt activation, and these defects were partially rescued by rapamycin or the selective p70S6K inhibitor PF‐4708671. Together, these findings identify an adipocyte MKK3‐p38β‐p70S6K axis that helps preserve insulin signaling during nutritional stress.
Authors
- Nuria Matesanz (ORCID: https://orcid.org/0000-0002-5756-3424)
- Juan Ignacio Jiménez‐Loygorri (ORCID: https://orcid.org/0000-0002-3065-9952)
- Alfonso Mora (ORCID: https://orcid.org/0000-0002-6397-4836)
- Rubén Nogueiras (ORCID: https://orcid.org/0000-0002-9976-9930)
- Edgar Bernardo (ORCID: https://orcid.org/0000-0002-0500-9632)
- Roger J. Davis (ORCID: https://orcid.org/0000-0002-0130-1652)
- Lourdes Hernández‐Cosido (ORCID: https://orcid.org/0000-0003-1359-7478)
- Leticia Herrera‐Melle (ORCID: https://orcid.org/0000-0002-9630-2219)
- Miguel Marcos (ORCID: https://orcid.org/0000-0003-1269-4487)
- J. Simon C. Arthur (ORCID: https://orcid.org/0000-0002-8135-1958)
- Guadalupe Sabio (ORCID: https://orcid.org/0000-0002-2822-0625)
- Ángel R. Nebreda (ORCID: https://orcid.org/0000-0002-7631-4060)
- Francisca Mulero (ORCID: https://orcid.org/0000-0001-9584-4211)
- Alba C. Arcones (ORCID: https://orcid.org/0000-0001-8182-4973)
- Tamara Parracho (ORCID: https://orcid.org/0000-0001-9283-4464)
- Luis Leiva‐Vega (ORCID: https://orcid.org/0000-0002-0050-8117)
- María Elena Rodríguez (ORCID: https://orcid.org/0009-0007-9776-8786)
- Marta Leon (ORCID: https://orcid.org/0009-0005-4170-341X)
- Paula Yong González
- Jorge‐Luis Torres
- Teresa Durán (ORCID: https://orcid.org/0009-0006-7153-4343)
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- University of Massachusetts Chan Medical School (US)
- University of Dundee (GB)
- Universidad de Salamanca (ES)
- Universidade de Santiago de Compostela (ES)
- Spanish National Centre for Cardiovascular Research (ES)
- Spanish National Cancer Research Centre (ES)
- Complejo Hospitalario de Salamanca (ES)
- Institute for Research in Biomedicine (ES)
- Barcelona Institute of Science and Technology (ES)
- Instituto de Investigación Biomédica de Salamanca (ES)
Publication Details
- Journal
- Advanced Science
- Published
- 2026-10-28
- DOI
- https://doi.org/10.1002/advs.202520388
- Primary Topic
- Adipokines, Inflammation, and Metabolic Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00